The invention relates to a novel polymorphic form of {4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid previously described in WO2009/065406. The compound may be used in treatment of a number of disorders or diseases associated with disturbances of CaSR activity.
Calcimimetics are small molecule allosteric activators of the calcium-sensing receptor (CaSR) [Urena, P.; Frazao, J. M. Calcimimetic agents: Review and perspectives. Kidney International (2003), 63, pp. s91-s96; Soudijn, W. et al. Allosteric modulation of G protein-coupled receptors: perspectives and recent developments. DDT (2004), 9, 752-758].
Calcimimetics have already been shown to be commercially useful for the treatment of hyperparathyroidism (HPT): The calcimimetic compound Cinacalcet® [Balfour, J. A. B. et al. Drugs (2005) 65(2), 271-281; Linberg et. al. J. Am. Soc. Nephrol (2005), 16, 800-807, Clinical Therapeutics (2005), 27(11), 1725-1751] has recently been launched for the treatment of secondary HPT in chronic kidney disease patients on dialysis and for the treatment of primary HPT in patients with parathyroid carcinoma. Thus, proof of concept for activators of calcium sensing receptor (CaSR) in humans has been achieved, and the clinical relevance is already well established. Other calcimimetic compounds were for example described in WO 94/018959, WO98/001417, WO05/065050, WO03/099814, WO03/099776, WO00/21910, WO01/34562, WO01/090069, WO97/41090, U.S. Pat. No. 6,001,884, WO96/12697, EP1203761, WO95/11221, WO93/04373, EP1281702, WO02/12181, WO04/069793, US2004242602, WO04/106296 and WO05/115975.
{4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid is part of a new promising class (WO2009/065406) of compounds displaying calcimimetic activity.
One important aspect of pharmaceutical production is the question of the physical form of the Active Pharmaceutical Ingredient (API). The physical form, such as the crystal form, of a drug substance or API used in a pharmaceutical formulation or medicament is important because different physical forms often display different fundamental properties such as solubility, dissolution rate, hygroscopicity, bioavailability, processability and stability. The existence of various solid forms, such as polymorphism or pseudopolymorphism can thereby affect the properties of the drug product.
Hence, a specific crystal form, including solvates and hydrates, might be preferable over another one. Furthermore certain forms may be preferable depending on the specific formulation and/or application. For example, the properties of a drug, such as the dissolution rate of the active ingredient, may be tuned by the proper choice of a certain crystal form, or mixtures of crystal forms in specific ratios.
A crystalline form of an API is usually preferred over a non-crystalline form, e.g. an amorphous form, in a drug formulation or during chemical processing due to its predictable properties. Crystalline forms have inter alia the advantage of greater chemical stability (pressure, heat and light), easier processability and handling. In particular the provision of a crystalline form is an important advantage during drug synthesis, especially on an industrial scale, since crystals are generally easier isolated from a reaction mixture.
Furthermore it is known that the crystallisation of a specific crystalline form of a compound in a particular solvent may result in an advantageous purification of the compound which would not be achieved by crystallisation of another form in a different solvent (partly due to differences in solubility properties of impurities in different solvents). Amorphous compounds, on the contrary, cannot be purified by recrystallisation, but will often require more expensive purification methods such as eg. preparative chromatography.
Various crystalline forms also differ in melting point, density, hardness, grinding properties, etc. and as a consequence a particular polymorphic form is preferred over another one depending on the specific application. Different crystalline forms have different stabilities in pharmaceutical formulations which depend on the excipients, vehicles, and other additives present in the dosage form. The instability of amorphous compounds or polymorphic forms which are not the most stable one represents in particular a problem when the drug substance is in suspension.
Accordingly while crystalline forms are generally preferred over non-crystalline forms of a drug substance, a specific crystalline form of a compound will be preferred depending on the various circumstances, such as its application or the process in which it is being used.
Sometimes a thermodynamically more stable form is preferred over a metastable form, sometime a metastable form which may have an increased dissolution rate is preferred.
WO2009/065406 describes the synthesis of {4-[(1R,3S)-3-(R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid, but does not discloses crystalline forms of the compound or the preparation of such forms. The application is silent as regards polymorphism and how to obtain a stable polymorphic form of {4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid.
WO2010/021351 describes the synthesis of {4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid derivatives but does not disclose crystalline forms of said derivatives.